Winkelstein et al. (2009) demonstrated alleviation of pain after nerve-root injury followed by application of salmon thrombin and salmon fibrin to the injury site. Nerve roots sit at the junction of the peripheral nervous system (PNS) and central nervous system (CNS) and contain elements of both systems. Therefore, CNS-mediated pain includes pain that could originate in either or both systems. Evidence was presented that the salmon-derived material was beneficial for pain resulting from injury to a nerve.
The present invention extends Winkelstein et al. by demonstrating a method of alleviating pain originating from tissue damage. This nociceptive pain in the peripheral nervous system signals the spinal cord and brain, and is therefore also CNS-mediated. Nociceptive pain includes the well-documented stimulation of peripheral pain fibers such as A- and C-fibers after surgery or other injury to skin, fascia, muscle, and bone.
Thrombin polymerizes fibrinogen to form a clot (fibrin) and is generally recognized as a hemostatic agent. Previous studies have shown that salmon thrombin and human thrombin are interchangeable for fibrin formation. Michaud et al 2002, emphasize the similarities of human and salmon thrombins. Comparison of these two thrombins showed similar primary structure and specific enzyme activity with respect to activation of fibrinogen, and therefore salmon thrombin performs well as a hemostatic agent (Rothwell et al. 2005). Hemostatic agents are indicated for many surgical procedures and injuries, and there is a wide selection available (Spotnitz al, 2008), but none address the accompanying pain. Bovine, human, and recombinant human thrombin are frequently used to control bleeding but these thrombins are pro-inflammatory in the CNS (Suo et al. 2004), and can in some cases exacerbate neuronal damage and pain (Wu et al, 2008). Thrombin can act on mammalian cells through protease activated receptors (PARs). The effect of these thrombin receptors on pain is complex, with some receptors on some cells inhibiting pain, and others promoting hyperalgesia (Garcia et al. 2010). In clinical practice however, mammalian thrombin is either ineffective for pain, or contraindicated as in cases of CNS injury. Therefore, the use of thrombin from any source as a treatment for pain is novel and represents a departure from current practice, which teaches against its use.
The pain of surgery and other tissue injury is most often treated with repeated injections of local anesthetics such as Marcaine® (bupivacaine), which can result in cardiovascular system toxicity (Mather, 2010), and opioids, which can lead to a host of problems including addiction. Therefore, there is a clear unmet clinical need for a safe, long-lasting, non-addictive substance for pain relief.